Vaccine

ABSTRACT

Vaccine comprising a peptide bound to a pharmaceutically acceptable carrier, said peptide having the amino acid sequence 
     
       
         
               
             
                 (SEQ ID NO: 1) 
               
               
               
             
                 (X 1 ) m  (X 2 ) n  (X 3 ) o  X 4  X 5  H P X 6   
                 (Formula I), 
               
           
              
             
          
           
              
             
          
         
       
         
         
           
             for treating and/or preventing a physical disorder associated with the renin-activated angiotensin system, wherein
           X 1  is G or D,   X 2  is A, P, M, G, or R,   
         
             X 3  is G, A, H, or V,
           X 4  is S, A, D, or Y,   X 5  is A, D, H, S, N, or I,   
         
             X 6  is A, L or F, 
             wherein m, n and o are independently 0 or 1 under the premise that when o is 0 m and n are 0 and when n is 0 m is 0, and wherein the peptide is not DRVYIHPF (SEQ ID NO:4).

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.13/386,603, which is the U.S. National Stage Application under U.S.C.§371 of International Application No. PCT/AT2010/000271, with aninternational filing date of Jul. 23, 2010. The content of the aforesaidapplication is relied upon and incorporated by reference in itsentirety.

REFERENCE TO A SEQUENCE LISTING SUBMITTED ELECTRONICALLY VIA EFS-WEB

The content of the sequence listing (Name:r56221-2010-07-23-seq_list_ST25, Size: 46,620 bytes; and Date ofCreation: Dec. 21, 2011) electronically submitted via EFS-Web isincorporated by reference in its entirety.

The present invention relates to a medicament to be used in the fieldsof medicine, immunology, molecular biology and virology preferentiallyto prevent and/or treat physical disorders associated with therenin-activated angiotensin system, preferably hypertension andhypertension-associated cardiovascular diseases (CVD).

The renin angiotensin system (RAS), also known as renin angiotensinaldosteron system (RAAS), is a hormone system that regulates differentphysiological processes in the body. RAS activity is initiated by thecleavage of the peptide angiotensinogen to the decapeptide angiotensin I(Ang I) by the enzyme renin. The key product of the renin system is theoctapeptide hormone angiotensin II (Ang II), which is formed from Ang Iby the angiotensin-converting enzyme (ACE). RAS plays a key role involume regulation and the maintenance of blood pressure. However,excessive activity of the renin system is associated with hypertensionand target organ damage.

In recent years it became clear that the renin angiotensin system (RAS)extends well beyond their classical role in blood pressure regulationand salt-water balance. Beside regulating the physiological andpathophysiological processes of cardiovascular and renin tissue, the RAShas been described to act on a number of additional tissues, including,brain, endocrine, sensory, fat and immune cells. Thus the RAS plays animportant role in physiological and pathophysiological processes ofthese tissues as well.

Since physiological and pathophysiological implications of the RAS areextremely broad medications targeting the RAS have become key clinicaltools in the treatment of cardiovascular and renal diseases, such ashypertension, heart failure and diabetic nephropthy. Moreover differentstudies show that blocking the RAS does not only influencecardiovascular diseases connected to high blood pressure but can alsoreduce cardiovascular events linked to inflammatory processes such asatherosclerosis. These basic research and animal studies stronglysupport angiotensin II as a proinflammatory mediator, which directlyinduces atherosclerotic plaque development and heart remodeling.

In addition, RAS seems to be central not only to the inflammatoryaspects of atherosclerosis but also of autoimmune diseases such asmultiple sclerosis.

Furthermore, evidence suggests that blockade of the renin-angiotensinsystem decreases the occurrence of new-onset diabetes and reduces therisk of diabetic complications. Other studies provide an overview of theeffects of Ang II leading to the development of insulin resistance andits implications for diabetes. Components of the renin-angiotensinsystem have a complex interaction with insulin action and thedevelopment and progression of metabolic diseases.

RAS, Inflammatory Disorders and Autoimmune Disorders (Atherosclerosisand Multiple Sclerosis)

Atherosclerosis is a chronic inflammatory disease, which involvesvascular cells, immune system, and several organs. Although leukocytes,endothelial and smooth muscle cells have been shown to play a crucialrole in atherosclerotic inflammation, recent evidence also supports adirect activity for cytokines and chemokines, factors that have beenshown to modulate inflammatory processes. Recent studies now suggest newinflammatory activities for the peptide hormone angiotensin II. Therenin-angiotensin system serves an important role in promotinginflammation, since angiotensin II induces proatherosclerotic cytokinesecretion and increases endothelial dysfunction. Angiotensin IIregulates not only cytokine, chemokine, and growth factor secretionwithin the arterial wall but regulates also the expression of adhesionmolecules (VCAM-1, ICAM-1, P-selectin). Beside this it has been shownthat the renin-angiotensin system can modulate the activation ofcomplement system in both atherosclerosis and renal injury. Thisinflammatory cascade activates the vascular inflammatory response byincreasing inflammatory cell recruitment to intima. Recruited cells canproduce angiotensin II, resulting in a positive feedback response, whichcan maintain this inflammatory vicious circle.

Recently different publications show that the intersection betweenchronic inflammatory diseases like multiple sclerosis (MS) and the mostcommon of all of the human chronic diseases, atherosclerosis, may go farbeyond the root “sclerosis”, which is shared in both their names. Theyshowed that the RAS also plays a major role in autoimmunity, exemplifiedby multiple sclerosis (MS) and its animal model, experimental autoimmuneencephalomyelitis (EAE). Using proteomics, the authors observed that RASis up-regulated in brain lesions of MS. Blocking angiotensin IIproduction with ACE inhibitors or inhibiting angiotensin II signalingwith angiotensin II receptor blockers suppressed autoreactive TH1 andTH17 cells and promoted antigen-specific CD4_FoxP3_ regulatory T cells(Treg cells). Treatment with ACE inhibitors induces abundant CD4 FoxP3 Tcells with sufficient potency to reverse paralytic EAE. Therefore,authors concluded that modulation of the RAS is an attractivetherapeutic strategy for application to human autoimmune diseases.

RAS and Cardiovascular Diseases—Hypertension

Cardiovascular disease (CVD) is the leading cause of death throughoutthe world. According to the World Health Organization (WHO)approximately 30% of all global deaths can be attributed to CVD. CVD iscaused by disorders of the heart and blood vessels and encompassesvarious manifestations. These include myocardial infarction, stroke,heart failure, and end stage renal disease. The most prevalent riskfactor for CVD is hypertension. More than a quarter of the world's adultpopulation had hypertension in 2000 and if appropriate action is nottaken, this numbers will increase continuously.

Hypertension, commonly referred to as high blood pressure is defined aschronically elevated blood pressure with a systolic blood pressure above140 mmHg and/or a diastolic blood pressure above 90 mmHg. Guidelinesdefined by the “Joint National Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pressure” suggest that personswith a blood pressure between 120 and 139 mmHg systolic and/or a bloodpressure between 80 and 89 mmHg diastolic should be consideredpre-hypertensive and require health-promoting changes to prevent CVD.Therefore, lowering the blood pressure is an important strategy toprevent CVD. As first step, blood pressure reduction can be achieved bychanges in life style targeting the primary factors like unhealthy diet,physical inactivity, and smoking. However, treatment of essentialhypertension requires specific therapies. A key regulator of the bloodpressure is the renin-angiotensin system (RAS) which has become anattractive target for therapeutic intervention. Thereforepharmaceuticals that specifically act on components of the RAS havebecome important clinical tools in the treatment of hypertension.

The RAS pathway is a cascade beginning with the cleavage ofangiotensinogen by renin. Renin is an aspartyl protease synthesized andstored primarily in the granules of juxtaglomerular cells in the kidneyand has high substrate specificity for angiotensinogen. Angiotensinogenis mainly formed and constitutively secreted into the circulation byhepatic cells. It is cleaved at the N-terminus by renin to form thedecapeptide Angiotensin I (Ang I; the 1-10 peptide) which is rapidlyconverted into the biological active octapeptide angiotensin II (Ang II;the 1-8 peptide). In contrast to Ang II, Ang I appears to have nobiological activity and exists solely as a precursor for Ang II.Cleavage of Ang I is mediated basically, but not exclusively by theangiotensin-converting enzyme (ACE). This membrane-boundmetalloproteinase is expressed on the surface of endothelial cells withthe highest concentrations found on the vascular epithelium in the lung.Besides ACE chymase has been shown to produce Ang II. Ang II can alsodirectly be generated from angiotensinogen by enzymes like tonin andcathepsin. In addition, other Ang I- and Ang II-derived, functionalpeptides can be found in the circulation. These are generated by amino-,carboxy- or endopeptidases and include Ang(1-9), Ang(1-7), Ang III (the2-8 peptide) and Ang IV (the 3-8 peptide). A carboxypeptidase, known asangiotensin-converting enzyme II (ACE2), acts on Ang I as well as AngII. ACE2 generates Ang1-9 from Ang I and Ang1-7 from Ang II. Ang1-9 canthen be further converted to Ang1-7 by ACE. In contrast to Ang II, whichelevates blood pressure and appears to be the major mediator of vascularremodeling in hypertension, Ang1-7 peptide promotes vasodilation and bythat may counteract the potentially detrimental actions of Ang II. Thepeptide Ang1-7 acts via its receptor the mas oncogen product (MAS).

Ang II and Ang 1-7 are considered as the main effector peptides of theRAS, while Ang III and Ang IV have some lesser activity (approximately40% of the activity of Ang II). The actions of Ang II are mediatedpredominantly by two seven transmembrane receptors termed Ang IIreceptors, type 1 (AT1; subtypes 1a and 1b) and type 2 (AT2). The AT1and AT2 subtypes bind Ang II similarly, but have a different cellularlocalization and are differentially expressed in diverse tissues. Mostof the Ang II hypertensinogenic actions are attributed to the AT1receptor.

Throughout the body Ang II is a potent vasoconstrictor. In the kidneysit constricts glomerular arterioles thereby increasing systemic arterialblood pressure and decreasing blood flow. In the adrenal cortex, itcauses the release of aldosterone which in turn causes the tubules inthe kidneys to reabsorb more sodium and water from the urine. It alsoacts on the central nervous system to increase a person's appetite forsalt and to make them feel thirsty. Additionally, Ang II stimulates therelease of Anti Diuretic Hormone (ADH).

The classical role of components of the RAS is to act as endocrinefactors in order to maintain blood pressure and electrolyte as well asfluid balance. In addition to this circulating RAS a localangiotensin-generating cascade exists in several tissues. The so-calledtissue RAS can act locally as a paracrine and/or autocrine factor andcan operate, in whole or in part, independently of the circulatingcounterpart.

Currently several drugs are on the market to treat hypertension. Theseencompass for example diuretics and calcium-channel blockers and includenumerous pharmaceuticals that specifically target components of the RAS.The latter include ACE inhibitors which act by binding to the activeside of ACE and interfering with the ability of the enzyme to bind andcleave its substrates. Characteristic side effects of ACE inhibitors aredry cough and first dose hypotension/angioneurotic oedema. Another classof pharmaceuticals that target the RAS is angiotensin receptor (AT1)blockers (ARBs). ARBs specifically interfere with the function of Ang IIby blocking the binding of angiotensin II to the AT1 receptor. Recently,a new compound targeting the RAS, namely Aliskerin a drug which inhibitsrenin has been released on the market.

In the art it is also suggested to use antagonists for Ang II which showa higher binding affinity to AT1 receptor than Ang II. In document WO2005/044313 A compounds are disclosed which can be used in the treatmentof heart diseases, diseases associated with fibrosis andatherosclerosis. The compounds disclosed in WO 2005/044313 A comprise anoctapeptide having the general formula X₁X₂VYIHPX₃ whereby X₁ may be anyamino acid residue, X₂ arginine or N-alkylated arginine or a mimetic ofarginine, and X₃ may be an amino acid residue containing a hydrophobicside chain. These compounds have a higher binding affinity to the AT1receptor than angiotensin II (antagonistic activity).

In GB 2001653 A a compound being derived from angiotensin II and havingthe general formula XRVYIHPY is disclosed, wherein X represents anα-aminooxy aliphatic acyl group and Y may be leucin, isoleuin, alanin orthreonin. Such a compound can be used in the treatment of renalhypertension.

WO 2002/087504 A, WO 2001/043761 A, WO 2001/098325 A and WO 2000/002905A provide compounds which function as angiotensin II analogues.

Although different drugs to treat hypertension are available on themarket, hypertension still remains inadequately handled. Poor overalltreatment success lies on the one hand in the asymptomatic nature ofhypertension and on the other side in the necessity for long-termtreatment with medications that requires at least once dailyself-administration.

Recently, active immunotherapy has become of increasing interest as apotential new strategy to treat hypertension and associated disorders.

The practicability of vaccination against components of the RAS to treathypertension has been shown in different animal models (Michel-J B etal., Am Heart J. 1989; 117:756). In one of the first approaches it hasbeen shown that vaccination against renin was effective in loweringblood pressure. However, this approach has not been pursued in followingyears since animals started to suffer from autoimmune nephritis(Michel-J B et al., Circulation. 1990; 81(6):1899-910). Other approachesaimed at inducing an immune response against components of the RAS thatare expressed as transmembrane proteins on the cell surface, such as ACEand AT₁R. Several research groups have investigated active immunizationagainst AT₁R. Although some studies report that antibodies against theN-terminus of the AT₁R can attenuate the development of hypertension inspontaneously hypertensive rats, most approaches had no significanteffect on blood pressure. Data on active immunization against ACE isvery limited. One report describes the vaccination of rabbits but only 1out of 50 animals made detectable anti ACE antibodies (Soffer-R L etal., Fed. Proc. 1983; 42(19):2735-9). No reports are available on activeimmunization against angiotensinogen, however several studies exploredthe feasibility of vaccination against angiotensin I and angiotensin II.

Vaccination with Ang I conjugated to carrier proteins (e.g. keyholelimpet haemocyanin (KLH)) led to the induction of high antigen-specifichumoral immune responses. In experimental settings using differentanimal models the vaccination-induced antibodies against angiotensin Iappeared to be functional, since (i) they were able to bind angiotensinI as revealed by Western blot analysis and (ii) the blood pressure wassignificantly reduced, indicating that the effects of angiotensin on theRAS were blocked (Downham et al., Br J Clin Pharmacol. 2003;56:505-12.). By contrast, in human healthy volunteers the blood pressurelowering effect was not seen (Downham et al., 2003). This finding wasfurther confirmed in a study with hypertensive patients who were treatedwith a 12 amino acid analogue of Ang I covalently linked to KLH andadsorbed to Alum (referred to as PMD3117) (Brown et al., Clin Sci. 2004;107:167-73). Importantly, this treatment regimen was well tolerated andinduced a long lasting, antigen-specific humoral immune response.Additionally, this treatment showed an effect on the renin system asdetected by changes in renin and aldosterone levels. However,vaccination with PMD3117 showed no influence on the blood pressure ascompared to the placebo control group (Brown et al., 2004). In contrast,a slightly different further development of this Ang I vaccine which wasdeveloped by Protherics and replaced Alum by a new adjuvant, namely CoVaccine HT™ did show an effect. Administration of this new vaccineformulation resulted in a 10-fold increase in anti-angiotensin antibodytiters in a preclinical setting and human healthy subjects showedchanges in systolic and diastolic blood pressure. However, bloodpressure was only slightly reduced and this only during rest periods butnot during phases of activity which would be of more importance.

Other approaches to induce antibodies that are able to block the RASused angiotensin II-derived peptides as antigens. In contrast to aprevious study where injection of Ang II-carrier protein conjugates didnot result in lowering blood pressure, vaccination with Ang II coupledto virus-like particles (VLP) led to the induction of a highanti-angiotensin specific humoral immune response, that was paralleledwith a statistically significant reduction of blood pressure (Ambühl etal., J Hypertension. 2007; 25:63-72.). In a recent clinical studyhowever, this blood pressure lowering effect could not be monitored uponvaccination using angiotensin II coupled to virus like particles,indicating that the induced humoral immune response induced by thispeptide vaccine might not be optimal or sufficient. Therefore, thereremains a need in the art to provide new and more effective vaccinestargeting angiotensin peptides.

It is an object of the present invention to provide a medication toprevent and treat conditions associated with elevated levels ofangiotensin II produced by the RAS on the basis of a vaccine.

It turned out that a vaccine comprising a peptide bound to apharmaceutically acceptable carrier, said peptide having the amino acidsequence

(SEQ ID NO: 1) (X₁)_(m) (X₂)_(n) (X₃)_(o) X₄ X₅ H P X₆ (Formula I),wherein

X₁ is G or D,

X₂ is A, P, M, G, or R,

X₃ is G, A, H, or V,

X₄ is S, A, D, or Y,

X₅ is A, D, H, S, N, or I,

X₆ is A, L or F,

wherein m, n and o are independently 0 or 1 under the premise that wheno is 0 m and n are 0 and when n is 0 m is 0, and wherein the peptide isnot DRVYIHPF (SEQ ID NO:4) can be suitably used for treating and/orpreventing a physical disorder associated with the renin-activatedangiotensin system.

Not only peptides having the amino acid sequence according to Formula Ican be used for treating and/or preventing a physical disorderassociated with the renin-activated angiotensin system, but alsopeptides having the amino acid sequences according to Formula II andIII. Therefore, another aspect of the present invention relates to avaccine comprising a peptide bound to a pharmaceutically acceptablecarrier, said peptide having the amino acid sequence

(SEQ ID NO: 2) (X₁)_(m) (X₂)_(n) (X₃)_(o) X₄ X₅ X₆ P X₇ (Formula II),for treating and/or preventing a physical disorder associated with therenin-activated angiotensin system, wherein

X₁ is G, A or D,

X₂ is A, P, M, G, or R,

X₃ is G, A, H, or V,

X₄ is S, A, D, or Y,

X₅ is A, D, H, S, N, or I,

X₆ is Y or H,

X₇ is A, V, L, I or F,

wherein m, n and o are independently 0 or 1 under the premise that wheno is 0 m and n are 0 and when n is 0 m is 0, and wherein the peptide isnot DRVYIHPF (SEQ ID NO:4).

According to a particularly preferred embodiment of the presentinvention the vaccine comprises a peptide having the amino acid sequence

(SEQ ID NO: 3) X₁X₂X₃X₄X₅X₆PX₇ (Formula III)which can be used for treating and/or preventing physical disordersassociated with the renin-activated angiotensin system, preferablyhypertension and hypertension-associated diseases, wherein

X₁ is G, A or D,

X₂ is A, P, M, G, or R,

X₃ is G, A, H, or V,

X₄ is S, A, D, or Y,

X₅ is A, D, H, S, N, or I,

X₆ is Y or H,

X₇ is A, V, L, I or F.

wherein the peptide is not DRVYIHPF (SEQ ID NO:4).

The vaccine of the present invention is able to induce specifically theformation of antibodies directed to angiotensin I or angiotensin II whencoupled to a carrier protein (or to a peptide containing a T cellepitope) and administered to a mammal. The peptides as outlined inFormulas I to III, may induce antibodies that recognize Ang II withhigher specificity than Ang I. Vaccines comprising a peptide having thesequence as outlined in Formulas I to III and having H, and L on theirC-terminus X₁X₂X₃X₄X₅X₆PX₇HL (both amino acids derived from Ang I), forinstance, induce antibodies that may recognize Ang I with higherspecificity than Ang II. This allows the specific targeting of eitheronly one species of angiotensin peptides or a combination thereof. Dueto the binding of these antibodies to angiotensinogen-derived peptidesin said mammals the level of angiotensin peptides can be influencedsignificantly, and thus these immunogens can be used in animmunotherapeutic approach to combat conditions associated with elevatedlevels of angiotensin II produced by the RAS or by other proteases (e.g.chymase). Without intending to be limited to any particular theory ofmode of molecular action, the peptide variants of the present inventionwill act as immunogens that can induce antibodies which bind to morethan one angiotensin peptide species, thus neutralizing all relevantspecies of angiotensin peptides at the same time. Alternatively, theinduced antibodies can specifically bind to the C-terminus ofangiotensin II. Under these conditions the induced antibodies willadditionally block the binding of angiotensin II to its receptor, theAT₁R.

The amino acid residues identified in Formulas I to III can be exchangedby the respective amino acid residues indicated above. The amino acidsequence obtained by said variation may comprise one, two, three, four,five, six or seven amino acid residues which are not identical to theoriginal Angiotensin II sequence (DRVYIHPF) (SEQ ID NO:4). Mostpreferably Formulas I to III may vary from the Angiotensin II sequenceby at least one, more preferably by at least two, amino acid residuesand by a maximum of seven, preferably by a maximum of six, morepreferably by a maximum of five, more preferably by a maximum of four,even more preferably by a maximum of three amino acid residues.

The peptides of the above identified Formulas may also comprise five,six, seven or eight amino acid residues (starting from X₁ or X₂ or X₃ tothe terminal amino acid residue).

The peptide according to the present invention may be a peptide with 5,6, 7 or 8 to 20, preferably with 5, 6, 7 or 8 to 15, in particular with5, 6, 7, 8 or 9, amino acid residues. The peptide of the presentinvention may also be part of a polypeptide or protein having up to 300,preferably up to 200, more preferably up to 150, even more preferably upto 100, amino acid residues.

The peptides of the present invention are not identical to the naturallyoccurring angiotensin II (DRVYIHPF) (SEQ ID NO:4). The vaccine of thepresent invention will elicit an immunological response in a host thatis reactive to angiotensin peptides.

The peptides of the present invention can be synthetically produced bychemical synthesis methods which are well known in the art, either as anisolated peptide or as a part of another peptide or polypeptide.Alternatively, the peptide can be produced in a microorganism whichproduces the peptide which is then isolated and if desired, furtherpurified. The peptide variant can be produced in microorganisms such asbacteria, yeast or fungi, in eukaryote cells such as a mammalian or aninsect cell, or in a recombinant virus vector such as adenovirus,poxvirus, herpesvirus, Simliki forest virus, baculovirus, bacteriophage,sindbis virus or sendai virus. Suitable bacteria for producing thecompound/peptide include E. coli, B. subtilis or any other bacteriumthat is capable of expressing peptides. Suitable yeast types forexpressing said compound/peptide include Saccharomyces cerevisiae,Schizosaccharomyces pombe, Candida, Pichia pastoris or any other yeastcapable of expressing peptides. Corresponding methods are well known inthe art. Also methods for isolating and purifying recombinantly producedpeptides are well known in the art and include e.g. as gel filtration,affinity chromatography, ion exchange chromatography etc.

To facilitate isolation of the peptide, a fusion polypeptide may be madewherein the peptide is translationally fused (covalently linked) to aheterologous polypeptide which enables isolation by affinitychromatography. Typical heterologous polypeptides are His-Tag (e.g.His6; 6 histidine residues), GST-Tag (Glutathione-S-transferase) etc.The fusion polypeptide facilitates not only the purification of thepeptide but may also prevent the degradation of said peptide duringpurification. If it is desired to remove the heterologous polypeptideafter purification, the fusion polypeptide may comprise a cleavage siteat the junction between the peptide and the heterologous polypeptide.The cleavage site consists of an amino acid sequence that is cleavedwith an enzyme specific for the amino acid sequence at the site (e.g.proteases).

“Peptide bound to a pharmaceutically acceptable carrier” and “peptidebound to a carrier”, as used herein refers to a peptide which is fusedto, or conjugated to a carrier. If the peptide of the present inventionis fused or conjugated (e.g. via carboxyl, amino, sulfhydryl, hydroxyl,imidazolyl, guanidyl or indolyl groups) to a protein carrier, a linkermay be provided between the peptide and the protein carrier.

According to a particularly preferred embodiment of the presentinvention the substituents of Formula I may be as follows:

X₁ is G or D,

X₂ is G, R, A, P or M

X₃ is A, V or G

X₄ is Y, A or S

X₅ is N, I, D, S or A and/or

X₆ is F.

According to a preferred embodiment of the present invention the peptidederived from Formula I is selected from the group consisting of GRVYIHPF(SEQ ID NO:6), DPVYIHPF (SEQ ID NO:7), DMVYIHPF (SEQ ID NO:8), DGVYIHPF(SEQ ID NO:9), DAVYIHPF (SEQ ID NO:10), DRGYIHPF (SEQ ID NO:11),DRAYIHPF (SEQ ID NO:12), DRHYIHPF (SEQ ID NO:13), DRVAIHPF (SEQ IDNO:14), DRVSIHPF (SEQ ID NO:15), DRVDIHPF (SEQ ID NO:16), DRVYAHPF (SEQID NO:17), DRVYNHPF (SEQ ID NO:18), DRVYDHPF (SEQ ID NO:19), DRVYHHPF(SEQ ID NO:20), DRVYSHPF (SEQ ID NO:21), DRVYIHPA (SEQ ID NO:23),DRVYIHPL (SEQ ID NO:25), DAAYIHPF (SEQ ID NO:27), DRAAIHPF (SEQ IDNO:28), DRVAAHPF (SEQ ID NO:29), DRAYAHPF (SEQ ID NO:30), DRAAAHPF (SEQID NO:31), DAAAIHPF (SEQ ID NO:34), DAGYIHPF (SEQ ID NO:37), DAHYIHPF(SEQ ID NO:38), DPGYIHPF (SEQ ID NO:39), DPAYIHPF (SEQ ID NO:40),DMGYIHPF (SEQ ID NO:41), DMAYIHPF (SEQ ID NO:42), DMHYIHPF (SEQ IDNO:43), DGGYIHPF (SEQ ID NO:44), DGAYIHPF (SEQ ID NO:45), DGHYIHPF (SEQID NO:46), DPVAIHPF (SEQ ID NO:47), DMVAIHPF (SEQ ID NO:49), DMVSIHPF(SEQ ID NO:50), DRGAIHPF (SEQ ID NO:51), DRHAIHPF (SEQ ID NO:52),DRGYAHPF (SEQ ID NO:53), DRGYDHPF (SEQ ID NO:54), DRGYHHPF (SEQ IDNO:55), DRGYSHPF (SEQ ID NO:56), DRGYNHPF (SEQ ID NO:57), DRAYDHPF (SEQID NO:58), DRAYHHPF (SEQ ID NO:59), DRAYSHPF (SEQ ID NO:60), DRAYNHPF(SEQ ID NO:61), DRHYAHPF (SEQ ID NO:62), DRHYSHPF (SEQ ID NO:63),DRHYNHPF (SEQ ID NO:64), DRHYDHPF (SEQ ID NO:65), DRHYHHPF (SEQ IDNO:66), DRGADHPF (SEQ ID NO:68), DRVAHHPF (SEQ ID NO:70), DRHADHPF (SEQID NO:71), GRGAIHPF (SEQ ID NO:72), DPGAIHPF (SEQ ID NO:75), DPGSIHPF(SEQ ID NO:77), DMGAIHPF (SEQ ID NO:78), DMGSIHPF (SEQ ID NO:79),GPGYIHPF (SEQ ID NO:80), GPGSIHPF (SEQ ID NO:82), GMGSIHPF (SEQ IDNO:83), DRGSIHPF (SEQ ID NO:84), DPHAIHPF (SEQ ID NO:85), DMHAIHPF (SEQID NO:86), GPHAIHPF (SEQ ID NO:87), GMHSIHPF (SEQ ID NO:90), PVYIHPF(SEQ ID NO:91), MVYIHPF (SEQ ID NO:92), GVYIHPF (SEQ ID NO:93), AVYIHPF(SEQ ID NO:94), RGYIHPF (SEQ ID NO:95), RAYIHPF (SEQ ID NO:96), RHYIHPF(SEQ ID NO:97), RVAIHPF (SEQ ID NO:98), RVSIHPF (SEQ ID NO:99), RVDIHPF(SEQ ID NO:100), RVYAHPF (SEQ ID NO:101), RVYNHPF (SEQ ID NO:102),RVYDHPF (SEQ ID NO:103), RVYHHPF (SEQ ID NO:104), RVYSHPF (SEQ IDNO:105), RVYIHPA (SEQ ID NO:107), RVYIHPL (SEQ ID NO:109), AAYIHPF (SEQID NO:111), RAAIHPF (SEQ ID NO:112), RVAAHPF (SEQ ID NO:113), RAYAHPF(SEQ ID NO:114), RAAAHPF (SEQ ID NO:115), AAAIHPF (SEQ ID NO:118),AGYIHPF (SEQ ID NO:121), AHYIHPF (SEQ ID NO: 122), PGYIHPF (SEQ IDNO:123), PAYIHPF (SEQ ID NO:124), MGYIHPF (SEQ ID NO:125), MAYIHPF (SEQID NO:126), MHYIHPF (SEQ ID NO:127), GGYIHPF (SEQ ID NO:128), GAYIHPF(SEQ ID NO:129), GHYIHPF (SEQ ID NO:130), PVAIHPF (SEQ ID NO:131),PVSIHPF (SEQ ID NO: 132), MVAIHPF (SEQ ID NO:133), MVSIHPF (SEQ IDNO:134), RGAIHPF (SEQ ID NO:135), RHAIHPF (SEQ ID NO: 136), RGYAHPF (SEQID NO:137), RGYDHPF (SEQ ID NO:138), RGYHHPF (SEQ ID NO:139), RGYSHPF(SEQ ID NO:140), RGYNHPF (SEQ ID NO:141), RAYDHPF (SEQ ID NO:142),RAYHHPF (SEQ ID NO:143), RAYSHPF (SEQ ID NO:144), RAYNHPF (SEQ IDNO:145), RHYAHPF (SEQ ID NO:146), RHYSHPF (SEQ ID NO:147), RHYNHPF (SEQID NO:148), RHYDHPF (SEQ ID NO:149), RHYHHPF (SEQ ID NO:150), RGADHPF(SEQ ID NO: 152), RGAHHPF (SEQ ID NO:153), RHADHPF (SEQ ID NO:155),RHSIHPF (SEQ ID NO:157), PGAIHPF (SEQ ID NO:159), RHAIHPF (SEQ ID NO:136), PGSIHPF (SEQ ID NO:161), MGAIHPF (SEQ ID NO:162), MGSIHPF (SEQ IDNO:163), RGSIHPF (SEQ ID NO:166), PHAIHPF (SEQ ID NO:167), MHAIHPF (SEQID NO:168), PHSIHPF (SEQ ID NO:169), MHSIHPF (SEQ ID NO:170), GYIHPF(SEQ ID NO:171), AYIHPF (SEQ ID NO:172), HYIHPF (SEQ ID NO:173), VYAHPF(SEQ ID NO:176), VYNHPF (SEQ ID NO:177), VYDHPF (SEQ ID NO:178), VYHHPF(SEQ ID NO:179), VYSHPF (SEQ ID NO:180), VYIHPA (SEQ ID NO:182), VYIHPL(SEQ ID NO:184), AAIHPF (SEQ ID NO:186), AYAHPF (SEQ ID NO:188), HYIHPF(SEQ ID NO:173), GAIHPF (SEQ ID NO:192), HAIHPF (SEQ ID NO:193), GYAHPF(SEQ ID NO:194), GYDHPF (SEQ ID NO:195), GYHHPF (SEQ ID NO:196), GYSHPF(SEQ ID NO:197), GYNHPF (SEQ ID NO:198), AYDHPF (SEQ ID NO:199), AYHHPF(SEQ ID NO:200), AYSHPF (SEQ ID NO:201), AYNHPF (SEQ ID NO:202), HYAHPF(SEQ ID NO:203), HYSHPF (SEQ ID NO:204), HYNHPF (SEQ ID NO:205), HYDHPF(SEQ ID NO:206), HYHHPF (SEQ ID NO:207), GAIHPF (SEQ ID NO:192), HSIHPF(SEQ ID NO:214), GSIHPF (SEQ ID NO:216), HAIHPF (SEQ ID NO:193), AIHPF(SEQ ID NO:218), SIHPF (SEQ ID NO:219), DIHPF (SEQ ID NO:220), YAHPF(SEQ ID NO:221), YNHPF (SEQ ID NO:222), YDHPF (SEQ ID NO:223), YHHPF(SEQ ID NO:224) and YSHPF (SEQ ID NO:225).

Particularly preferred peptides are DPVYIHPF (SEQ ID NO:7), DMVYIHPF(SEQ ID NO:8), DGVYIHPF (SEQ ID NO:9), DAVYIHPF (SEQ ID NO:10), DRGYIHPF(SEQ ID NO:11), DRAYIHPF (SEQ ID NO:12), DRHYIHPF (SEQ ID NO:13),DRVAIHPF (SEQ ID NO:14), DRVYAHPF (SEQ ID NO: 17), DRVYNHPF (SEQ IDNO:18), DRVYDHPF (SEQ ID NO:19), DRVYSHPF (SEQ ID NO:21), DRVYIHPL (SEQID NO:25), DAAYIHPF (SEQ ID NO:27), DRAAIHPF (SEQ ID NO:28), DRVAAHPF(SEQ ID NO:29), DRAYAHPF (SEQ ID NO:30), DAGYIHPF (SEQ ID NO:37),DAHYIHPF (SEQ ID NO:38), DPGYIHPF (SEQ ID NO:39), DPAYIHPF (SEQ IDNO:40), DMGYIHPF (SEQ ID NO:41), DMAYIHPF (SEQ ID NO:42), DMHYIHPF (SEQID NO:43), DGGYIHPF (SEQ ID NO:44), DGAYIHPF (SEQ ID NO:45), DGHYIHPF(SEQ ID NO:46), DMVSIHPF (SEQ ID NO:50), DRGAIHPF (SEQ ID NO:51),DRGYAHPF (SEQ ID NO:53), DRGYDHPF (SEQ ID NO:54), DRGYSHPF (SEQ IDNO:56), DRGYNHPF (SEQ ID NO:57), DRAYDHPF (SEQ ID NO:58), DRAYSHPF (SEQID NO:60), DRAYNHPF (SEQ ID NO:61), DRHYAHPF (SEQ ID NO:62), DRHYSHPF(SEQ ID NO:63), DRHYNHPF (SEQ ID NO:64), DRHYDHPF (SEQ ID NO:65),GPGYIHPF (SEQ ID NO:80), GPGSIHPF (SEQ ID NO:82), DRGSIHPF (SEQ IDNO:84), PVYIHPF (SEQ ID NO:91), GVYIHPF (SEQ ID NO:93), AVYIHPF (SEQ IDNO: 94), RGYIHPF (SEQ ID NO: 95), RAYIHPF (SEQ ID NO: 96), RHYIHPF (SEQID NO:97), RVAIHPF (SEQ ID NO:98), RVSIHPF (SEQ ID NO:99), RVDIHPF (SEQID NO:100), RVYAHPF (SEQ ID NO:101), RVYNHPF (SEQ ID NO:102), RVYDHPF(SEQ ID NO:103), RVYSHPF (SEQ ID NO:105), RVYIHPL (SEQ ID NO:109),AAYIHPF (SEQ ID NO:111), RAAIHPF (SEQ ID NO:112), RVAAHPF (SEQ IDNO:113), RAYAHPF (SEQ ID NO:114), AGYIHPF (SEQ ID NO:121), AHYIHPF (SEQID NO:122), PGYIHPF (SEQ ID NO:123), PAYIHPF (SEQ ID NO:124), GGYIHPF(SEQ ID NO:128), GAYIHPF (SEQ ID NO:129), GHYIHPF (SEQ ID NO:130),PVSIHPF (SEQ ID NO:132), MVSIHPF (SEQ ID NO:134), RGAIHPF (SEQ IDNO:135), RGYAHPF (SEQ ID NO:137), RGYDHPF (SEQ ID NO:138), RGYSHPF (SEQID NO:140), RGYNHPF (SEQ ID NO:141), RAYDHPF (SEQ ID NO:142), RAYSHPF(SEQ ID NO:144), RAYNHPF (SEQ ID NO:145), RHYAHPF (SEQ ID NO:146),RHYSHPF (SEQ ID NO:147), RHYNHPF (SEQ ID NO:148), RHYDHPF (SEQ IDNO:149), RHSIHPF (SEQ ID NO:157), PGAIHPF (SEQ ID NO:159), RHAIHPF (SEQID NO:136), PGSIHPF (SEQ ID NO:161), MGAIHPF (SEQ ID NO:162), MGSIHPF(SEQ ID NO:163), MGYIHPF (SEQ ID NO:125), RGSIHPF (SEQ ID NO:166),PHAIHPF (SEQ ID NO:167), MHAIHPF (SEQ ID NO:168), PHSIHPF (SEQ IDNO:169), MHSIHPF (SEQ ID NO:170), GYIHPF (SEQ ID NO:171), AYIHPF (SEQ IDNO:172), VYAHPF (SEQ ID NO:176), VYNHPF (SEQ ID NO:177), VYDHPF (SEQ IDNO:178), VYSHPF (SEQ ID NO:180), AAIHPF (SEQ ID NO:186), AYAHPF (SEQ IDNO:188), HYIHPF (SEQ ID NO:173), GAIHPF (SEQ ID NO:192), GYAHPF (SEQ IDNO:194), GYDHPF (SEQ ID NO:195), GYSHPF (SEQ ID NO:197), GYNHPF (SEQ IDNO:198), AYDHPF (SEQ ID NO:199), AYSHPF (SEQ ID NO:201), AYNHPF (SEQ IDNO:202), GAIHPF (SEQ ID NO:192), GSIHPF (SEQ ID NO:216).

Even more preferred peptides are DPVYIHPF (SEQ ID NO:7), DMVYIHPF (SEQID NO:8), DGVYIHPF (SEQ ID NO:9), DAVYIHPF (SEQ ID NO:10), DRGYIHPF (SEQID NO:11), DRAYIHPF (SEQ ID NO:12), DRHYIHPF (SEQ ID NO:13), DRVYIHPL(SEQ ID NO:25), DAAYIHPF (SEQ ID NO:27), DRAAIHPF (SEQ ID NO:28),DRVAAHPF (SEQ ID NO:29), DRAYAHPF (SEQ ID NO:30), DAGYIHPF (SEQ IDNO:37), DAHYIHPF (SEQ ID NO:38), DPGYIHPF (SEQ ID NO:39), DPAYIHPF (SEQID NO:40), DMGYIHPF (SEQ ID NO:41), DMAYIHPF (SEQ ID NO:42), DMHYIHPF(SEQ ID NO:43), DGGYIHPF (SEQ ID NO:44), DGAYIHPF (SEQ ID NO:45),DGHYIHPF (SEQ ID NO:46), DMVSIHPF (SEQ ID NO:50), DRGAIHPF (SEQ IDNO:51), DRGYAHPF (SEQ ID NO:53), DRGYDHPF (SEQ ID NO:54), DRGYSHPF (SEQID NO:56), DRGYNHPF (SEQ ID NO:57), DRAYDHPF (SEQ ID NO:58), DRAYSHPF(SEQ ID NO:60), DRAYNHPF (SEQ ID NO:61), GPGYIHPF (SEQ ID NO:80),PVYIHPF (SEQ ID NO: 91), GVYIHPF (SEQ ID NO:93), RGYIHPF (SEQ ID NO:95),RAYIHPF (SEQ ID NO:96), RVSIHPF (SEQ ID NO:99), RVYIHPL (SEQ ID NO:109),AAYIHPF (SEQ ID NO:111), RAAIHPF (SEQ ID NO:112), RAYAHPF (SEQ IDNO:114), AGYIHPF (SEQ ID NO:121), PGYIHPF (SEQ ID NO:123), PAYIHPF (SEQID NO:124), GAYIHPF (SEQ ID NO:129), PVSIHPF (SEQ ID NO:132), MVSIHPF(SEQ ID NO:134), RGAIHPF (SEQ ID NO:135), RGYAHPF (SEQ ID NO:137),RGYSHPF (SEQ ID NO:140), GYIHPF (SEQ ID NO:171), whereby the mostpreferred peptides are DPVYIHPF (SEQ ID NO:7), DMVYIHPF (SEQ ID NO:8),DAAYIHPF (SEQ ID NO:27), DRAAIHPF (SEQ ID NO:28), DRAYAHPF (SEQ IDNO:30), DAGYIHPF (SEQ ID NO:37), DPGYIHPF (SEQ ID NO:39), DGAYIHPF (SEQID NO:45), DMVSIHPF (SEQ ID NO:50), DRGAIHPF (SEQ ID NO:51), DRGYDHPF(SEQ ID NO:54), DRGYSHPF (SEQ ID NO:56), PVYIHPF (SEQ ID NO:91), GVYIHPF(SEQ ID NO:93), AAYIHPF (SEQ ID NO:111), RAAIHPF (SEQ ID NO:112),RAYAHPF (SEQ ID NO: 114), PGYIHPF (SEQ ID NO:123), PVSIHPF (SEQ IDNO:132), MVSIHPF (SEQ ID NO:134), RGAIHPF (SEQ ID NO:135).

According to a preferred embodiment of the present invention

X₁ of Formula II and III is G, A or D,

X₂ of Formula II and III is G, A, P, M, or R

X₃ of Formula II and III is G, A, H, or V

X₄ of Formula II and III is S, A, D, or Y

X₅ of Formula II and III is A, D, H, S, N or I

X₆ of Formula II and III is Y or H

X₇ of Formula II and III is A, V, L, I or F.

The amino acid residues mentioned above are particularly preferredsubstitutes.

The peptides of the present invention may comprise a truncation at theirN-terminus, so that these peptides miss the first, second and/or thirdamino acid residue.

The peptide is preferably selected from the group consisting of GRVYIHPF(SEQ ID NO:6), DPVYIHPF (SEQ ID NO:7), DMVYIHPF (SEQ ID NO:8), DGVYIHPF(SEQ ID NO:9), DAVYIHPF (SEQ ID NO:10), DRGYIHPF (SEQ ID NO:11),DRAYIHPF (SEQ ID NO:12), DRHYIHPF (SEQ ID NO:13), DRVAIHPF (SEQ IDNO:14), DRVSIHPF (SEQ ID NO:15), DRVDIHPF (SEQ ID NO:16), DRVYAHPF (SEQID NO: 17), DRVYNHPF (SEQ ID NO:18), DRVYDHPF (SEQ ID NO:19), DRVYHHPF(SEQ ID NO:20), DRVYSHPF (SEQ ID NO:21), DRVYIYPF (SEQ ID NO:22),DRVYIHPA (SEQ ID NO:23), DRVYIHPV (SEQ ID NO:24), DRVYIHPL (SEQ IDNO:25), DRVYIHPI (SEQ ID NO:26), DAAYIHPF (SEQ ID NO:27), DRAAIHPF (SEQID NO:28), DRVAAHPF (SEQ ID NO:29), DRAYAHPF (SEQ ID NO:30), DRAAAHPF(SEQ ID NO:31), ARAAIHPF (SEQ ID NO:32), ARVAAHPF (SEQ ID NO:33),DAAAIHPF (SEQ ID NO:34), DAAAAHPF (SEQ ID NO:35), DAVAAHPF (SEQ IDNO:36), DAGYIHPF (SEQ ID NO:37), DAHYIHPF (SEQ ID NO:38), DPGYIHPF (SEQID NO:39), DPAYIHPF (SEQ ID NO:40), DMGYIHPF (SEQ ID NO:41), DMAYIHPF(SEQ ID NO:42), DMHYIHPF (SEQ ID NO:43), DGGYIHPF (SEQ ID NO:44),DGAYIHPF (SEQ ID NO:45), DGHYIHPF (SEQ ID NO:46), DPVAIHPF (SEQ IDNO:47), DPVSIHPF (SEQ ID NO:48), DMVAIHPF (SEQ ID NO:49), DMVSIHPF (SEQID NO:50), DRGAIHPF (SEQ ID NO:51), DRHAIHPF (SEQ ID NO:52), DRGYAHPF(SEQ ID NO:53), DRGYDHPF (SEQ ID NO:54), DRGYHHPF (SEQ ID NO:55),DRGYSHPF (SEQ ID NO:56), DRGYNHPF (SEQ ID NO:57), DRAYDHPF (SEQ IDNO:58), DRAYHHPF (SEQ ID NO:59), DRAYSHPF (SEQ ID NO:60), DRAYNHPF (SEQID NO:61), DRHYAHPF (SEQ ID NO:62), DRHYSHPF (SEQ ID NO:63), DRHYNHPF(SEQ ID NO:64), DRHYDHPF (SEQ ID NO:65), DRHYHHPF (SEQ ID NO:66),DRHYIYPF (SEQ ID NO:67), DRGADHPF (SEQ ID NO:68), DRGAHHPF (SEQ IDNO:69), DRVAHHPF (SEQ ID NO:70), DRHADHPF (SEQ ID NO:71), GRGAIHPF (SEQID NO:72), GRHSIHPF (SEQ ID NO:73), GRHADYPF (SEQ ID NO:74), DPGAIHPF(SEQ ID NO:75), GRHAIHPF (SEQ ID NO:76), DPGSIHPF (SEQ ID NO:77),DMGAIHPF (SEQ ID NO:78), DMGSIHPF (SEQ ID NO:79), GPGYIHPF (SEQ IDNO:80), GMGYIHPF (SEQ ID NO:81), GPGSIHPF (SEQ ID NO:82), GMGSIHPF (SEQID NO:83), DRGSIHPF (SEQ ID NO:84), DPHAIHPF (SEQ ID NO:85), DMHAIHPF(SEQ ID NO:86), GPHAIHPF (SEQ ID NO:87), GMHAIHPF (SEQ ID NO:88),GPHSIHPF (SEQ ID NO:89), and GMHSIHPF (SEQ ID NO:90).

Truncated versions missing the first N-terminal amino acid residue arepreferably selected from the group consisting of PVYIHPF (SEQ ID NO:91),MVYIHPF (SEQ ID NO:92), GVYIHPF (SEQ ID NO:93), AVYIHPF (SEQ ID NO:94),RGYIHPF (SEQ ID NO:95), RAYIHPF (SEQ ID NO:96), RHYIHPF (SEQ ID NO:97),RVAIHPF (SEQ ID NO:98), RVSIHPF (SEQ ID NO:99), RVDIHPF (SEQ ID NO:100),RVYAHPF (SEQ ID NO:101), RVYNHPF (SEQ ID NO:102), RVYDHPF (SEQ IDNO:103), RVYHHPF (SEQ ID NO:104), RVYSHPF (SEQ ID NO:105), RVYIYPF (SEQID NO:106), RVYIHPA (SEQ ID NO:107), RVYIHPV (SEQ ID NO:108), RVYIHPL(SEQ ID NO:109), RVYIHPI (SEQ ID NO:110), AAYIHPF (SEQ ID NO:111),RAAIHPF (SEQ ID NO:112), RVAAHPF (SEQ ID NO:113), RAYAHPF (SEQ IDNO:114), RAAAHPF (SEQ ID NO:115), RAAIHPF (SEQ ID NO:112), RVAAHPF (SEQID NO:113), AAAIHPF (SEQ ID NO:118), AAAAHPF (SEQ ID NO:119), AVAAHPF(SEQ ID NO:120), AGYIHPF (SEQ ID NO:121), AHYIHPF (SEQ ID NO:122),PGYIHPF (SEQ ID NO:123), PAYIHPF (SEQ ID NO:124), MGYIHPF (SEQ IDNO:125), MAYIHPF (SEQ ID NO:126), MHYIHPF (SEQ ID NO:127), GGYIHPF (SEQID NO:128), GAYIHPF (SEQ ID NO:129), GHYIHPF (SEQ ID NO:130), PVAIHPF(SEQ ID NO:131), PVSIHPF (SEQ ID NO:132), MVAIHPF (SEQ ID NO:133),MVSIHPF (SEQ ID NO:134), RGAIHPF (SEQ ID NO:135), RHAIHPF (SEQ IDNO:136), RGYAHPF (SEQ ID NO:137), RGYDHPF (SEQ ID NO:138), RGYHHPF (SEQID NO:139), RGYSHPF (SEQ ID NO:140), RGYNHPF (SEQ ID NO:141), RAYDHPF(SEQ ID NO:142), RAYHHPF (SEQ ID NO:143), RAYSHPF (SEQ ID NO:144),RAYNHPF (SEQ ID NO:145), RHYAHPF (SEQ ID NO:146), RHYSHPF (SEQ IDNO:147), RHYNHPF (SEQ ID NO:148), RHYDHPF (SEQ ID NO:149), RHYHHPF (SEQID NO:150), RHYIYPF (SEQ ID NO:151), RGADHPF (SEQ ID NO:152), RGAHHPF(SEQ ID NO:153), RVAHHPF (SEQ ID NO:154), RHADHPF (SEQ ID NO:155),RHSIHPF (SEQ ID NO:157), RHADYPF (SEQ ID NO:158), PGAIHPF (SEQ IDNO:159), RHAIHPF (SEQ ID NO:136), PGSIHPF (SEQ ID NO:161), MGAIHPF (SEQID NO:162), MGSIHPF (SEQ ID NO:163), RGSIHPF (SEQ ID NO:166), PHAIHPF(SEQ ID NO:167), MHAIHPF (SEQ ID NO:168), PHSIHPF (SEQ ID NO:169), andMHSIHPF (SEQ ID NO:170).

Truncated versions missing the first two N-terminal amino acid residuesare preferably selected from the group consisting of GYIHPF (SEQ IDNO:171), AYIHPF (SEQ ID NO:172), HYIHPF (SEQ ID NO:173), VAIHPF (SEQ IDNO:174), VSIHPF (SEQ ID NO:191), VDIHPF (SEQ ID NO:175), VYAHPF (SEQ IDNO:176), VYNHPF (SEQ ID NO:177), VYDHPF (SEQ ID NO:178), VYHHPF (SEQ IDNO:179), VYSHPF (SEQ ID NO:180), VYIYPF (SEQ ID NO:181), VYIHPA (SEQ IDNO:182), VYIHPV (SEQ ID NO:183), VYIHPL (SEQ ID NO:184), VYIHPI (SEQ IDNO:185), AAIHPF (SEQ ID NO:186), VAAHPF (SEQ ID NO:187), AYAHPF (SEQ IDNO:188), AAAHPF (SEQ ID NO:189), HYIHPF (SEQ ID NO:173), GAIHPF (SEQ IDNO:192), HAIHPF (SEQ ID NO:193), GYAHPF (SEQ ID NO:194), GYDHPF (SEQ IDNO:195), GYHHPF (SEQ ID NO:196), GYSHPF (SEQ ID NO:197), GYNHPF (SEQ IDNO:198), AYDHPF (SEQ ID NO:199), AYHHPF (SEQ ID NO:200), AYSHPF (SEQ IDNO:201), AYNHPF (SEQ ID NO:202), HYAHPF (SEQ ID NO:203), HYSHPF (SEQ IDNO:204), HYNHPF (SEQ ID NO:205), HYDHPF (SEQ ID NO:206), HYHHPF (SEQ IDNO:207), HYIYPF (SEQ ID NO:208), GADHPF (SEQ ID NO:209), GAHHPF (SEQ IDNO:210), VAHHPF (SEQ ID NO:211), HADHPF (SEQ ID NO:212), GAIHPF (SEQ IDNO:192), HSIHPF (SEQ ID NO:214), HADYPF (SEQ ID NO:215), GSIHPF (SEQ IDNO:216), and HAIHPF (SEQ ID NO:193).

Truncated versions missing the first three N-terminal amino acidresidues are preferably selected from the group consisting of AIHPF (SEQID NO:218), SIHPF (SEQ ID NO:219), DIHPF (SEQ ID NO:220), YAHPF (SEQ IDNO:221), YNHPF (SEQ ID NO:222), YDHPF (SEQ ID NO:223), YHHPF (SEQ IDNO:224), YSHPF (SEQ ID NO:225), YIYPF (SEQ ID NO:226), YIHPA (SEQ IDNO:227), YIHPV (SEQ ID NO:228), YIHPL (SEQ ID NO:229), YIHPI (SEQ IDNO:230), AAHPF (SEQ ID NO:231), ADHPF (SEQ ID NO:232), AHHPF (SEQ IDNO:233), and ADYPF (SEQ ID NO:234).

According to a preferred embodiment of the present invention at leastone cysteine residue is bound to the N-terminus of the amino acidsequences according to Formula I, II and/or III and all specificpeptides mentioned above.

The peptide of the present invention may further comprise at least onecysteine residue at its N-terminus. This cysteine residue may serve as areactive group in order to bind the peptide to another molecule or acarrier. For instance, this group may be used to bind the peptide to acarrier protein. The cysteine residue may alternatively be bound to theC-terminus of the peptide of the present invention.

The peptide of the present invention is bound to a carrier, preferablyprotein carrier.

In order to enhance the production of angiotensin peptide specificantibodies in a mammal the compound of the present invention is bound toa carrier.

According to a preferred embodiment of the present invention the carrieris selected from the group consisting of keyhole limpet haemocyanin(KLH), tetanus toxoid (TT) or diphtheria toxin (DT) or any other proteinor peptide containing T cell epitopes.

According to a preferred embodiment of the present invention the peptideis coupled to a pharmaceutically acceptable carrier, preferably KLH(Keyhole Limpet Haemocyanin), tetanus toxoid, albumin-binding protein,bovine serum albumin, a dendrimer (MAP; Biol. Chem. 358: 581), peptidelinkers (or flanking regions) as well as the adjuvant substancesdescribed in Singh et al., Nat. Biotech. 17 (1999), 1075-1081 (inparticular those in Table 1 of that document), and O'Hagan et al.,Nature Reviews, Drug Discovery 2 (9) (2003), 727-735 (in particular theendogenous immuno-potentiating compounds and delivery systems describedtherein), or mixtures thereof. The conjugation chemistry (e.g. viaheterobifunctional compounds such as GMBS and of course also others asdescribed in “Bioconjugate Techniques”, Greg T. Hermanson) in thiscontext can be selected from reactions known to the skilled man in theart. Moreover, the vaccine composition may be formulated with anadjuvant, preferably a low soluble aluminium composition, in particularaluminium hydroxyide. Of course, also adjuvants like MF59 aluminiumphosphate, calcium phosphate, cytokines (e.g., IL-2, IL-12, GM-CSF),saponins (e.g., QS21), MDP derivatives, CpG oligos, LPS, MPL,polyphosphazenes, emulsions (e.g., Freund's, SAF), liposomes, virosomes,iscoms, cochleates, PLG microparticles, poloxamer particles, virus-likeparticles, heat-labile enterotoxin (LT), cholera toxin (CT), mutanttoxins (e.g., LTK63 and LTR72), microparticles and/or polymerizedliposomes may be used.

According to a preferred embodiment of the present invention the peptideis formulated with an adjuvant, preferably adsorbed to alum.

In a related embodiment, the invention is useful for the prevention ortreatment of diseases, disorders or conditions associated with the RAS,including but not limited to hypertension, stroke, infarction, kidneyfailure, congestive heart failure, vascular damage or retinalhemorrhage. In addition to that immunization using peptides enclosed inthe embodiment of the present invention can be used to treat or preventatherosclerotic plaque formation, arterial thrombosis events and eventsassociated with vascular inflammation. Beside this treatment ofautoimmune diseases such as multiple sclerosis can be performed usingpeptides enclosed in the embodiment of the present invention.

The vaccine of the present invention may be administered subcutaneously,intramuscularly, intradermally, intravenously (see e.g. “Handbook ofPharmaceutical Manufacturing Formulations”, Sarfaraz Niazi, CRC PressInc, 2004). Depending on the route of administration, the medicament maycomprise respective carriers, adjuvants and/or excipients.

The vaccine according to the present invention contains the compoundaccording to the invention in an amount of from 0.1 ng to 10 mg,preferably 10 ng to 1 mg, in particular 100 ng to 100 μg, or,alternatively, e.g. 100 fmol to 10 μmol, preferably 10 pmol to 1 μmol,in particular 100 pmol to 100 nmol. The compound or peptide of thepresent invention is administered to a mammal in an amount of preferably100 ng to 1 mg, more preferably 1 μg to 500 μg, even more preferably 10μg to 100 μg, in particular 20 to 40 or 30 μg, per doses. Typically, thevaccine may also contain auxiliary substances, e.g. buffers, stabilizersetc.

Yet, another aspect of the present invention relates to the use of apeptide according to the present invention for the manufacture of amedicament for treating and/or preventing physical disorders associatedwith the renin-activated angiotensin system, preferably hypertension andhypertension-associated diseases.

The abbreviations for the amino acid residues disclosed in the presentinvention follow the IUPAC recommendations:

Amino Acid 3-Letter Code 1-Letter Code Alanine Ala A Arginine Arg RAsparagine Asn N Aspartic Asp D Cysteine Cys C Glutamic Glu E GlutamineGln Q Glycine Gly G Histidine His H Isoleucine Ile I Leucine Leu LLysine Lys K Methionine Met M Phenylalanine Phe F Proline Pro P SerineSer S Threonine Thr T Tryptophan Trp W Tyrosine Tyr Y Valine Val V

The present invention is further illustrated in the following figuresand examples, however, without being restricted thereto.

FIG. 1 shows the immunogenicity of peptide variants for position 1 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 2 shows the immunogenicity of peptide variants for position 2 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 3 shows the immunogenicity of peptide variants for position 3 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 4 shows the immunogenicity of peptide variants for position 4 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 5 shows the immunogenicity of peptide variants for position 5 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 6 shows the immunogenicity of peptide variants for position 6 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 7 shows the immunogenicity of peptide variants for position 7 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 8 shows the immunogenicity of peptide variants for position 8 ofAng II peptide CDRVYIHPF (SEQ ID NO:235).

FIG. 9 shows the immunogenicity of peptide variants where two or moreamino acids were replaced by alanine.

FIG. 10 shows the immunogenicity of peptide variants where three aminoacids were replaced on different positions using favorable amino acidsubstitutes for these positions.

FIG. 11 shows the immunogenicity of peptide variants where two to fouramino acids were replaced on different positions using favorable aminoacid substitutes for these positions.

FIG. 12 shows the immunogenicity of truncated angiotensin VARIOTOPEversions missing the first N-terminal amino acid.

FIG. 13 shows the immunogenicity of truncated angiotensin VARIOTOPEversions missing the first two or three N-terminal amino acids.

In each Figure, on the X-axis sera derived from animals immunized withindicated peptides are listed. On the Y-axis relative titers of inducedsera are shown. Titers derived from Ang II treated animals were set as100%. Titers were calculated as the sera dilution giving half-maximalbinding (i.e. OD_(max)/2). White bars indicate titers against thepeptides that were used for vaccination while black bars representtiters against the Ang II peptide.

EXAMPLES Example 1 Positional-Scanning of the Ang II Peptide

Angiotensin II (Ang II), a key component of the blood pressureregulating RAS was chosen as target for a vaccination approach.Therefore, peptides which are able to induce a humoral immune responsethat targets angiotensin II have been identified and selected.

The term “positional scanning” refers to a technology thatsystematically substitutes the amino acid (AA) residues at each positionwithin a certain protein or peptide region with other AAs. Thistechnology has been used and applied so far only for protein-proteininteraction studies, peptide-protein interaction studies and/or forstudying the functionality of peptide or protein domains.

The positional scanning technology was now transferred into and appliedin the field of immunology to identify appropriate VARIOTOPEs for theoctapeptide Ang II (DRVYIHPF) (SEQ ID NO:4). The aim of this example wasto identify AA for each position that support or at least do notinterfere with the induction of a polyclonal/oligoclonal humoral immuneresponse that targets the Ang II peptide.

Therefore, in a first set of experiments each position in the Ang IIsequence was systematically replaced by amino acids having similar ordifferent features (see Table 1 for position 2). Subsequently all thesepeptides were chemically linked via an additional N-terminal cystein tothe protein carrier keyhole limpet haemocyanin (KLH) and administratedto mice (BALB/c) together with Alum as adjuvant. Sera from vaccinatedmice were used to analyze the immunogenicity of indicated peptides. Forthis purpose a peptide based ELISA assay was used to define sera titersagainst the injected peptide (i.e. Ang II peptide variants, VARIOTOPEs)as well as to define the binding capacity of the obtained sera againstthe Ang II peptide.

TABLE 1 Peptide variants by amino acid substitution for  position 2Position 1 2 3 4 5 6 7 8 C D R V Y I H P F Ang II SEQ ID NO: 235 C D A VY I H P F aliphatic non-polar neutral SEQ ID NO: 236 C D E V Y I H P Fopposed charge polar acidic SEQ ID NO: 237 C D F V Y I H P F aromaticnon-polar neutral SEQ ID NO: 238 C D H V Y I H P F aromatic polar basicSEQ ID NO: 239 C D K V Y I H P F aliphatic polar basic SEQ ID NO: 240 CD M V Y I H P F aliphatic non-polar neutral SEQ ID NO: 241 C D V V Y I HP F aliphatic non-polar neutral SEQ ID NO: 242 C D Y V Y I H P Faromatic polar neutral SEQ ID NO: 243 C D P V Y I H P F ring non-polarneutral SEQ ID NO: 244

In the Figures (FIGS. 1 to 8 for position 1 to position 8) the resultsderived from these experiments are shown. On the X-axis sera derivedfrom animals immunized with indicated peptides are listed. On the Y-axisrelative titers of induced sera are shown. Titers derived from Ang IItreated animals were set as 100%. Titers were calculated as the seradilution giving half-maximal binding (i.e. OD_(max)/2). White barsindicate titers against the peptides that were used for vaccinationwhile black bars represent titers against the Ang II peptide.

Although all tested Ang II peptide variants for position 1 were able toinduce antibodies which bound to the injected peptide (FIG. 1),indicating that the amino acid exchange did not abrogate theirimmunogenicity completely, some peptide variants induced sera thatshowed a significantly lower titer (peptide variants having an aromaticamino acid exchange). In contrast to this, the peptide variant with G onposition 1 seems to have the capacity to induce sera-titers against theinjected peptide that are almost twice as high as sera-titers derivedfrom Ang II treated animals. Reactivity against Ang II is roughlyincreased by 50% using this variant. Sera derived from peptide variantscontaining A, T, E, N, R or H on first position do not differsignificantly from sera derived from Ang II peptide. Aromatic oraliphatic residue on position 1 such as L, F, Y seem to be lessfavorable for inducing an immune response that recognizes Ang II.

Therefore, position 1 may contain the following AA:

-   -   the original AA D    -   the amino acids G, A    -   amino acids that are polar such as E, N, R, H.

As outlined in FIG. 2 using peptides for immunization where the arginineon position 2 was replaced by P or M increased the titer and also thereactivity to Ang II. Peptides with e.g. R to A or R to K substitutionevoked sera that showed the same titer as sera induced by the Ang IIpeptide. These results indicate that a P or M instead of an R onposition 2 is more favorable for inducing a humoral immune response. Aand K for example seem to be as good as R.

Position 2 may contain the following AA:

-   -   the original AA R    -   the non-polar and neutral AAs P, M, G and A    -   amino acids that are polar such as E, H, K

Position 3 may contain following AA:

-   -   the original AA V    -   The AAs G and H (most favorable)    -   non-polar and neutral AAs such as A    -   AA aliphatic AA such as L    -   amino acids that are polar such as E, H, K

On Position 4 the original AA Y can be substituted by all AAirrespective of their characteristics.

The aromatic AAs Y and W and the AA P cannot substitute the original AAI on position 5. All other AA can be used for this purpose.

The results derived from peptides where the H on position 6 was replacedby indicated amino-acids are shown in FIG. 6. Substitution of thearomatic amino-acid H by other aromatic amino acids such as W, and Yresulted in peptides that have the capacity to induce sera that seem torecognize Ang II even better than the peptide used for vaccination. Forpeptides with non aromatic amino-acid substitutions on position 6 thereactivity of evoked sera to Ang II is considerably diminished (up to60%). These results indicate that on position 6 aromatic amino acid canbe placed (but not F).

Position 6 may contain following AA:

-   -   the original AA H    -   amino acids that contain an aromatic side chain such as Y, W

Position 7 may contain following AA:

-   -   the original AA P    -   alternatively amino acids that contain an aromatic side chain        such as F, W, H may potentially be used

Position 8 may contain following AA:

-   -   the original AA F    -   the AA A, L, I, V, P, M

Example 2 Combined Exchanges of Two or More AA-Positions in Ang IISequence Using Alanine

To prove the results derived from the first in vivo experiments wherethe positional scanning approach was performed, and to test whethercombined AA exchanges on different positions might either be additive,when neutral or favorable AA replace the original AA, or subtractive,when less favorable AA are combined, two or more amino acids in the AngII sequence were replaced. For this purpose in a next set of experimentsthe amino acid alanine was used (Table 2). Alanine has been defined as afavorable-exchange AA for position 4 (FIG. 4), a neutral-exchange AA forposition 1, 2, 3, 5, and for position 8 (FIGS. 1 to 3, 5, 8 and 9). Forposition 6 and 7 the exchange of the original AAs H and P, respectively,to alanine appeared to be less favorable (FIGS. 6, 7 and 9). Therefore,peptide variants containing alanine on position 4 (favorable exchange)in combination with 1 to 3, 5, and 8 (neutral exchange), can be expectedto induce titers against Ang II that are higher or have at least thesame value as titers from sera evoked by Ang II peptide. Peptidevariants containing alanine on position 1 to 3, 5 and 8 should induce atleast an immune response that recognizes Ang II equally well as seraevoked by Ang II peptide. Peptide variants with alanine exchanges onposition 6 and 7 (less favorable exchange amino acid for thesepositions) can be expected to evoke sera with diminished reactivityagainst Ang II.

All peptides listed in Table 2 were again chemically linked via theN-terminus to KLH adsorbed to Alum and injected s.c. into experimentalanimals (BALB/c mice). Sera were analyzed by ELISA and antibodyresponses induced by the peptide variants were compared to that oneinduced by the original peptide.

TABLE 2 Example for peptide variants by amino  acid substitutionexchanged exchanged sequence position amino acid C-DRVYIHPF(SEQ ID NO: 235) C-DAAVIHPF 2, 3 R, V C-DRAAIHPF 3, 4 V, Y C-DRVAAHPF4, 5 Y, I C-DRVYAAPF 5, 6 I, H C-DRVYIHAA 7, 8 P, F C-DRAAAHPF 3, 4, 5V, Y, I C-DRAYAHPF 3, 5 V, I C-DRAAAHPA 3, 4, 5, 8 V, Y, I, F C-DAVYIAPF2, 6 R, H C-DAVYIAAF 2, 6, 7 R, H, P C-DAVYIAAA 2, 6, 7, 8 R, H, P, F

All alanine-substituted peptide variants were able to induce antibodieswhich bind to the injected peptide, indicating that the amino acidexchange did not abrogate their immunogenicity (FIG. 9). But the titersof the sera induced by C-DAVYIAAF, are lower compared to the titersinduced by the other antigens, indicating that the combined exchange ofindicated AA by alanine is less favorable for immunogenicity of thepeptides (FIG. 9).

Analyzing the reactivity of peptide variant-induced sera (Table 2)against Ang II revealed that sera induced by the following peptidesshowed diminished reactivity to Ang II: C-DRVYAAPF, C-DRVYIHAA,C-DRAAAHAF, C-DAVYIAPF, C-DAVYIAAF, C-DAVYIAAA, (FIG. 9). These resultsindicate that Ang II-peptide-variants having at least one alaninesubstitution at position 6 or position 7 (alanine as a non-favorable AAexchange for these positions), induce sera that show diminishedreactivity to Ang II. This is in line with results obtained inpositional scanning experiments.

Alanine substitutions on the position 1-5 of the Ang II molecule (forthose positions A has been defined as neutral or favorable AA exchange)do not interfere with reactivity to Ang II. Alanine-substitution onthese positions led to the induction of titers which were above to thatobtained with Ang II. This effect was seen especially when Y at position4 was replaced by alanine (FIG. 9).

Investigation of various alanine-modified Ang II epitopes in Wistar ratsshowed similar results. This indicates that the results are not onlyrestricted to mice but can also be transferred to another species.

Example 3 Combination of Favorable AAs on Different Positions forSelection of Angiotensin VARIOTOPEs

In next experiments AA combinations of favorable and/or neutral AA foreach position have been tested. As can be seen in FIGS. 10 and 11 aminoacid exchanges on different positions using favorable amino acidsselected during positional scanning experiments result in the formationof VARIOTOPEs that are able to induce humoral immune responses toangiotensin II that are comparable or higher to that response induced byangiotensin II.

Example 4 Truncated Angiotensin VARIOTOPE Versions Missing the FirstN-Terminal Amino Acid Residues

In next experiments truncated versions of angiotensin VARIOTOPEs havebeen tested. As can be seen in FIGS. 12 and 13 shortening angiotensinVARIOTOPEs (selected as outlined above) on their N-termini does notabrogate their capacity to induce humoral immune responses toangiotensin II that are comparable or higher to that response induced byangiotensin II.

1. A pharmaceutical composition for inducing an immune responsecomprising a peptide bound to a pharmaceutically acceptable carrier,wherein said peptide has the amino acid sequence (SEQ ID NO: 1)(X₁)_(m) (X₂)_(n) (X₃)_(o) X₄ X₅ HP X₆ (Formula I),

wherein X₁ is G or D, X₂ is A, P, M, G, or R, X₃ is G, A, H, or V, X₄ is5, A, D, or Y, X₅ is A, D, H, S, N, or I, X₆ is A, L or F, wherein m, nand o are independently 0 or 1 under the premise that when o is 0 m andn are 0 and when n is 0 m is 0, and wherein the peptide is not DRVYIHPF(SEQ ID NO:4), and wherein said pharmaceutical composition is fortreating and/or preventing a physical disorder associated with therennin-activated angiotensin system.
 2. The pharmaceutical compositionaccording to claim 1, wherein the peptide is selected from the groupconsisting of GRVYIHPF (SEQ ID NO:6), DPVYIHPF (SEQ ID NO:7), DMVYIHPF(SEQ ID NO:8), DGVYIHPF (SEQ ID NO:9), DAVYIHPF (SEQ ID NO:10), DRGYIHPF(SEQ ID NO:11), DRAYIHPF (SEQ ID NO:12), DRHYIHPF (SEQ ID NO:13),DRVAIHPF (SEQ ID NO:14), DRVSIHPF (SEQ ID NO:15), DRVDIHPF (SEQ IDNO:16), DRVYAHPF (SEQ ID NO: 17), DRVYNHPF (SEQ ID NO:18), DRVYDHPF (SEQID NO:19), DRVYHHPF (SEQ ID NO:20), DRVYSHPF (SEQ ID NO:21), DRVYIHPA(SEQ ID NO:23), DRVYIHPL (SEQ ID NO:25), DAAYIHPF (SEQ ID NO:27),DRAAIHPF (SEQ ID NO:28), DRVAAHPF (SEQ ID NO:29), DRAYAHPF (SEQ IDNO:30), DRAAAHPF (SEQ ID NO:31), DAAAIHPF (SEQ ID NO:34), DAGYIHPF (SEQID NO:37), DAHYIHPF (SEQ ID NO:38), DPGYIHPF (SEQ ID NO:39), DPAYIHPF(SEQ ID NO:40), DMGYIHPF (SEQ ID NO:41), DMAYIHPF (SEQ ID NO:42),DMHYIHPF (SEQ ID NO:43), DGGYIHPF (SEQ ID NO:44), DGAYIHPF (SEQ IDNO:45), DGHYIHPF (SEQ ID NO:46), DPVAIHPF (SEQ ID NO:47), DMVAIHPF (SEQID NO:49), DMVSIHPF (SEQ ID NO:50), DRGAIHPF (SEQ ID NO:51), DRHAIHPF(SEQ ID NO:52), DRGYAHPF (SEQ ID NO:53), DRGYDHPF (SEQ ID NO:54),DRGYHHPF (SEQ ID NO:55), DRGYSHPF (SEQ ID NO:56), DRGYNHPF (SEQ IDNO:57), DRAYDHPF (SEQ ID NO:58), DRAYHHPF (SEQ ID NO:59), DRAYSHPF (SEQID NO:60), DRAYNHPF (SEQ ID NO:61), DRHYAHPF (SEQ ID NO:62), DRHYSHPF(SEQ ID NO:63), DRHYNHPF (SEQ ID NO:64), DRHYDHPF (SEQ ID NO:65),DRHYHHPF (SEQ ID NO:66), DRGADHPF (SEQ ID NO:68), DRVAHHPF (SEQ IDNO:70), DRHADHPF (SEQ ID NO:71), GRGAIHPF (SEQ ID NO:72), DPGAIHPF (SEQID NO:75), DPGSIHPF (SEQ ID NO:77), DMGAIHPF (SEQ ID NO:78), DMGSIHPF(SEQ ID NO:79), GPGYIHPF (SEQ ID NO:80), GPGSIHPF (SEQ ID NO:82),GMGSIHPF (SEQ ID NO:83), DRGSIHPF (SEQ ID NO:84), DPHAIHPF (SEQ IDNO:85), DMHAIHPF (SEQ ID NO:86), GPHAIHPF (SEQ ID NO:87), GMHSIHPF (SEQID NO:90), PVYIHPF (SEQ ID NO: 91), MVYIHPF (SEQ ID NO: 92), GVYIHPF(SEQ ID NO: 93), AVYIHPF (SEQ ID NO: RGYIHPF (SEQ ID NO: 95), RAYIHPF(SEQ ID NO: 96), RHYIHPF (SEQ ID NO: 97), RVAIHPF (SEQ ID NO: 98),RVSIHPF (SEQ ID NO: 99), RVDIHPF (SEQ ID NO: 100), RVYAHPF (SEQ ID NO:101), RVYNHPF (SEQ ID NO: 102), RVYDHPF (SEQ ID NO: 103), RVYHHPF (SEQID NO: 104), RVYSHPF (SEQ ID NO: 105), RVYIHPA (SEQ ID NO:107), RVYIHPL(SEQ ID NO: 109), AAYIHPF (SEQ ID NO: 111), RAAIHPF (SEQ ID NO: 112),RVAAHPF (SEQ ID NO: 113), RAYAHPF (SEQ ID NO: 114), RAAAHPF (SEQ ID NO:115), AAAIHPF (SEQ ID NO: 118), AGYIHPF (SEQ ID NO: 121), AHYIHPF (SEQID NO: 122), PGYIHPF (SEQ ID NO:164), PAYIHPF (SEQ ID NO: 124), MGYIHPF(SEQ ID NO:125), MAYIHPF (SEQ ID NO: 126), MHYIHPF (SEQ ID NO: 127),GGYIHPF (SEQ ID NO: 128), GAYIHPF (SEQ ID NO: 129), GHYIHPF (SEQ ID NO:130), PVAIHPF (SEQ ID NO: 131), PVSIHPF (SEQ ID NO: 132), MVAIHPF (SEQID NO: 133), MVSIHPF (SEQ ID NO: 134), RGAIHPF (SEQ ID NO:156), RHAIHPF(SEQ ID NO: 136), RGYAHPF (SEQ ID NO: 137), RGYDHPF (SEQ ID NO: 138),RGYHHPF (SEQ ID NO: 139), RGYSHPF (SEQ ID NO: 140), RGYNHPF (SEQ ID NO:141), RAYDHPF (SEQ ID NO: 142), RAYHHPF (SEQ ID NO: 143), RAYSHPF (SEQID NO: 144), RAYNHPF (SEQ ID NO: 145), RHYAHPF (SEQ ID NO: 146), RHYSHPF(SEQ ID NO: 147), RHYNHPF (SEQ ID NO: 148), RHYDHPF (SEQ ID NO: 149),RHYHHPF (SEQ ID NO: 150), RGADHPF (SEQ ID NO: 152), RGAHHPF (SEQ ID NO:153), RHADHPF (SEQ ID NO: 155), RHSIHPF (SEQ ID NO:157), PGAIHPF (SEQ IDNO:159), RHAIHPF (SEQ ID NO: 136), PGSIHPF (SEQ ID NO:161), MGAIHPF (SEQID NO:162), MGSIHPF (SEQ ID NO:163), RGSIHPF (SEQ ID NO:166), PHAIHPF(SEQ ID NO:167), MHAIHPF (SEQ ID NO:168), PHSIHPF (SEQ ID NO:169),MHSIHPF (SEQ ID NO:170), GYIHPF (SEQ ID NO:171), AYIHPF (SEQ ID NO:172),HYIHPF (SEQ ID NO:190), VYAHPF (SEQ ID NO:176), VYNHPF (SEQ ID NO:177),VYDHPF (SEQ ID NO:178), VYHHPF (SEQ ID NO:179), VYSHPF (SEQ ID NO:180),VYIHPA (SEQ ID NO:182), VYIHPL (SEQ ID NO:184), AAIHPF (SEQ ID NO:186),AYAHPF (SEQ ID NO:188), HYIHPF (SEQ ID NO:190), GAIHPF (SEQ ID NO:192),HAIHPF (SEQ ID NO:193), GYAHPF (SEQ ID NO:194), GYDHPF (SEQ ID NO:195),GYHHPF (SEQ ID NO:196), GYSHPF (SEQ ID NO:197), GYNHPF (SEQ ID NO:198),AYDHPF (SEQ ID NO:199), AYHHPF (SEQ ID NO:200), AYSHPF (SEQ ID NO:201),AYNHPF (SEQ ID NO:202), HYAHPF (SEQ ID NO:203), HYSHPF (SEQ ID NO:204),HYNHPF (SEQ ID NO:205), HYDHPF (SEQ ID NO:206), HYHHPF (SEQ ID NO:207),GAIHPF (SEQ ID NO:192), HSIHPF (SEQ ID NO:214), GSIHPF (SEQ ID NO:216),HAIHPF (SEQ ID NO:193), AIHPF (SEQ ID NO:218), SIHPF (SEQ ID NO:219),DIHPF (SEQ ID NO:220), YAHPF (SEQ ID NO:221), YNHPF (SEQ ID NO:222),YDHPF (SEQ ID NO:223), YHHPF (SEQ ID NO:224) and YSHPF (SEQ ID NO:225).3. The pharmaceutical composition Vaccine according to claim 1, whereinat least one cysteine residue is bound to the N-terminus of the aminoacid sequence according to Formula I.
 4. The pharmaceutical compositionaccording to claim 1, wherein said carrier is a protein carrier.
 5. Thepharmaceutical composition according to claim 4, wherein said proteincarrier is selected from the group consisting of keyhole limpethaemocyanin (KLH), tetanus toxoid (TT) and diphtheria toxin (DT).
 6. Thepharmaceutical composition according to claim 1, wherein saidcomposition further comprises an adjuvant.
 7. The pharmaceuticalcomposition according to claim 1, wherein said physical disorderassociated with the renin-activated angiotensin system is selected fromthe group consisting of hypertension, stroke, infarction, kidneyfailure, congestive heart failure, atherosclerosis, vascular damage,retinal hemorrhage, and autoimmune diseases, and multiple sclerosis. 8.(canceled)
 9. The pharmaceutical composition according to claim 6,wherein said adjuvant is alum.
 10. A method for treating a patienthaving or being at risk of a physical disorder associated with therenin-activated angiotensin system, wherein an efficient amount of acomposition according to any one of claim 1 is administered to saidpatient.
 11. The method according to claim 10, wherein said physicaldisorder associated with the renin-activated angiotensin system ishypertension or a hypertension-associated disease.
 12. The methodaccording to claim 10, wherein said physical disorder associated withthe renin-activated angiotensin system is selected from the groupconsisting of hypertension, stroke, infarction, kidney failure,congestive heart failure, atherosclerosis, vascular damage, retinalhemorrhage and an autoimmune disease wherein the autoimmune disease ismultiple sclerosis.